2. Academic Validation
  3. Identification of the SARS-unique domain of SARS-CoV-2 as an antiviral target

Identification of the SARS-unique domain of SARS-CoV-2 as an antiviral target

  • Nat Commun. 2023 Jul 6;14(1):3999. doi: 10.1038/s41467-023-39709-6.
Bo Qin # 1 2,  Ziheng Li # 1 2,  Kaiming Tang # 3 4,  Tongyun Wang 4,  Yubin Xie 4,  Sylvain Aumonier 5,  Meitian Wang 5,  Shuofeng Yuan 6 7,  Sheng Cui 8 9
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology Chinese Academy of Medical Sciences & Peking Union Medical College, 100730, Beijing, China.
  • 2 Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, 100730, Beijing, China.
  • 3 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • 4 Department of Microbiology, Li Ka Shing, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • 5 Swiss Light Source at the Paul Scherrer Institute, 5232, Villigen, Switzerland.
  • 6 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. yuansf@hku.hk.
  • 7 Department of Microbiology, Li Ka Shing, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. yuansf@hku.hk.
  • 8 NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology Chinese Academy of Medical Sciences & Peking Union Medical College, 100730, Beijing, China. cui.sheng@ipb.pumc.edu.cn.
  • 9 Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, 100730, Beijing, China. cui.sheng@ipb.pumc.edu.cn.
  • # Contributed equally.
PMID: 37414753 DOI: 10.1038/s41467-023-39709-6
Abstract

SARS-CoV-2 nsp3 is essential for viral replication and host responses. The SARS-unique domain (SUD) of nsp3 exerts its function through binding to viral and host proteins and RNAs. Herein, we show that SARS-CoV-2 SUD is highly flexible in solution. The intramolecular disulfide bond of SARS-CoV SUD is absent in SARS-CoV-2 SUD. Incorporating this bond in SARS-CoV-2 SUD allowed crystal structure determination to 1.35 Å resolution. However, introducing this bond in SARS-CoV-2 genome was lethal for the virus. Using biolayer interferometry, we screened compounds directly binding to SARS-CoV-2 SUD and identified theaflavin 3,3'-digallate (TF3) as a potent binder, Kd 2.8 µM. TF3 disrupted the SUD-guanine quadruplex interactions and exhibited anti-SARS-CoV-2 activity in Vero E6-TMPRSS2 cells with an EC50 of 5.9 µM and CC50 of 98.5 µM. In this work, we provide evidence that SARS-CoV-2 SUD harbors druggable sites for Antiviral development.

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